Identification of novel androgen receptor inhibitors for the treatment of castration resistant prostate cancer
Abstract
Interest in developing androgen receptor (AR) inhibitors with novel mechanism of action for the treatment of prostate cancer (PCa) is on the rise since the commercial anti-androgens (including recently approved drug, Enzalutamide) face clinical limitations. Current therapies fail over a period of time because they all target mutation-prone androgen binding pocket on AR to which the receptor has already developed effective resistance mechanisms. Hence, there is a pressing need for novel therapeutics that inhibit the AR through alternative modes of action. To address this problem, we have used in silico drug design methodology to create new drugs that act on an entirely different site on the AR, a recently identified co-activator site called binding function-3 (BF3). This dissertation describes the discovery and development of novel anti-androgens directed towards the BF3 surface of the AR. These inhibitors were developed through a series of computational experiments followed by extensive biological validations. Based on the activity profile of the identified inhibitors, it can be anticipated that these drug prototypes will lay a foundation for the development of alternative or supplementary small-molecule therapies capable of combating PCa even in its drug resistant forms. Because the emergence of castration resistance is the lethal end stage of the disease, we anticipate that the thesis work will eventually have a substantial impact on the survival of prostate cancer…
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